Urayama Kevin Y, Thompson Pamela D, Taylor Malcolm, Trachtenberg Elizabeth A, Chokkalingam Anand P
School of Public Health, University of California , Berkeley, CA , USA ; Center for Clinical Epidemiology, St. Luke's Life Science Institute , Tokyo , Japan.
Cancer Immunogenetics, St. Mary's Hospital, University of Manchester , Manchester , UK.
Front Oncol. 2013 Dec 12;3:300. doi: 10.3389/fonc.2013.00300.
The enduring suspicion that infections and immunologic response may play a role in the etiology of childhood leukemia, particularly acute lymphoblastic leukemia (ALL), is now supported, albeit still indirectly, by numerous epidemiological studies. The cumulative evidence includes, for example, descriptive observations of a peculiar peak incidence at age 2-5 years for ALL in economically developed countries, clustering of cases in situations of population mixing associated with unusual patterns of personal contacts, associations with various proxy measures for immune modulatory exposures early in life, and genetic susceptibility conferred by variation in genes involved in the immune system. In this review, our focus is the extended major histocompatibility complex (MHC), an approximately 7.6 Mb region that is well-known for its high-density of expressed genes, extensive polymorphisms exhibiting complex linkage disequilibrium patterns, and its disproportionately large number of immune-related genes, including human leukocyte antigen (HLA). First discovered through the role they play in transplant rejection, the classical HLA class I (HLA-A, -B, and -C) and class II (HLA-DR, HLA-DQ, and HLA-DP) molecules reside at the epicenter of the immune response pathways and are now the targets of many disease susceptibility studies, including those for childhood leukemia. The genes encoding the HLA molecules are only a minority of the over 250 expressed genes in the xMHC, and a growing number of studies are beginning to evaluate other loci through targeted investigations or utilizing a mapping approach with a comprehensive screen of the entire region. Here, we review the current epidemiologic evidence available to date regarding genetic variation contained within this highly unique region of the genome and its relationship with childhood ALL risk.
长期以来，人们一直怀疑感染和免疫反应可能在儿童白血病，尤其是急性淋巴细胞白血病（ALL）的病因中起作用。现在，众多流行病学研究为这一怀疑提供了支持，尽管仍然是间接的。累积的证据包括，例如，在经济发达国家，ALL在2至5岁时出现特殊的发病率高峰的描述性观察结果；在与不寻常的个人接触模式相关的人口混合情况下病例的聚集；与生命早期免疫调节暴露的各种替代指标的关联；以及免疫系统相关基因变异所赋予的遗传易感性。在本综述中，我们关注的是扩展的主要组织相容性复合体（MHC），这是一个约7.6兆碱基的区域，以其高密度的表达基因、表现出复杂连锁不平衡模式的广泛多态性以及数量极多的免疫相关基因（包括人类白细胞抗原（HLA））而闻名。经典的HLA I类分子（HLA - A、- B和- C）和II类分子（HLA - DR、HLA - DQ和HLA - DP）最初是通过它们在移植排斥中的作用被发现的，它们位于免疫反应途径的中心，现在是许多疾病易感性研究的目标，包括儿童白血病的研究。编码HLA分子的基因只是xMHC中超过250个表达基因中的少数，越来越多的研究开始通过针对性研究或利用对整个区域进行全面筛选的定位方法来评估其他基因座。在这里，我们综述了目前关于这个基因组高度独特区域内所含遗传变异及其与儿童ALL风险关系的流行病学证据。
